Anti-viral agents, such as the 2', 3'-dideoxynucleosides, have been seen as being of increasing importance in the treatment of disease. Such agents, are believed to function as chain-terminators, after intracellular phosphorylation to their 5'-triphosphates and incorporation into newly synthesized viral DNA by reverse transcriptase. It is generally believed that the lack of the 3' hydroxy group, essential for phosphodiester bond formation, contributes to their function. Such agents are thought to inhibit viral reverse transcriptase much more strongly than cellular DNA polymerase .alpha.. An example of such agent is AZT, the 3'-azido derivative of thymidine, which is believed to exert its anti HIV activity through this mechanism.
As clinical experience with agents such as AZT grows, it has been recognized that though the drug does not appear to cure AIDS, it does provide considerable therapeutic benefit to patients with AIDS or AIDS related complex (ARC). Its major drawback however is its severe bone marrow toxicity, which can lead to anemia, leukopenia and neutropenia. Although AZT is orally effective, it is expensive, has a short half-life and must be taken continuously every several hours at a dose of 250 mg or more.
Other nucleoside analogs, particularly 2', 3'-dideoxycytidine (ddC) and 2', 3'-dideoxyadenosine, have been found to be effective in inhibiting viral replication in this group of agents. Phase I and II trials with ddC has revealed much less bone marrow suppression with this agent as compared to AZT, however, peripheral neuropathy poses a special problem and appears to comprise the dose limiting toxicity of this drug.
Recently, AIDS patients were given weekly alternating regimes of AZT and ddC with encouraging results. Since the two drugs have different toxicity profiles, this mode of administration may permit adequate recovery from toxicity without compromising anti-viral activity in some patients. Other combination modalities of AZT and ddC are in clinical trials.
Currently available nucleoside analogs exhibit therapeutic benefits but also have many recognized shortcomings including short plasma half-life, insufficient penetration into the central nervous system, low therapeutic index, low potential for metabolic activation and/or high susceptibility to catabolism, and the emergence of clinical resistance. Thus, there is a continuing demand for more effective antiviral agents for use in the treatment of AIDS and related viral infections. To overcome these difficulties, a variety of prodrugs of antiviral agents have been synthesized and examined for therapeutic values.
For purposes of this specification by the term "prodrug" as used herein is meant a derivative of an active form of a known composition which derivative, when administered to a mammal, is gradually converted to the active form to produce a better therapeutic response and/or a reduced toxicity level.
The term "transient" as used herein describes the action of time-dependent conversion to the active form of a composition from its prodrug derivative, by chemical hydrolysis or other means including but not limited to enzymatic action, in such a manner that the active form is released from the derivative and the residue which remains of the derivative is essentially nontoxic and/or is metabolized to nontoxic metabolic by-products.
An object of this invention is to provide new, transient lipophilic dialkylaminomethylene prodrug derivatives, useful as chemotherapeutic agents which exhibit prolonged duration of action and decreased cellular and systemic toxicities.
A further object of this invention is to provide new lipophilic dialkylaminomethylene prodrug derivatives demonstrating an increased ability to cross biological membranes, particularly the "blood brain barrier."
A still further object of the invention is to provide new dialkylaminomethylene prodrug derivatives demonstrating varying degrees of lipophilicity and susceptibility to hydrolysis, permitting the optimization of pharmacokinetic properties and therapeutic effectiveness.
A still further object of the invention is to provide new compounds suitable as topical, in vitro, disinfectants.
These and other objects of this invention will become apparent from the following description of the invention.